46 A biochemical process once thought to play a minor role in cancer is now emerging as a major player in liver tumour development, according to a study published in Biochemical Pharmacology. The process, known as palmitoylation, involves attaching a fatty acid to proteins. This subtle modification appears to influence nearly every aspect of liver cancer, from tumour growth and metastasis to treatment resistance. Researchers from Chengdu University and the Chinese Academy of Medical Sciences have found that faulty palmitoylation may help liver cancer cells survive, spread and resist drugs. Their review highlights a growing body of evidence linking the modification to known cancer pathways, including those regulating gene expression, cell metabolism and immune evasion. The liver cancer subtype known as hepatocellular carcinoma is notoriously difficult to treat. Although chemotherapy and immunotherapy remain standard approaches, their effectiveness is often undermined by the cancer’s adaptability. The new findings suggest that the root of this adaptability may lie in enzymes called ZDHHCs, which regulate palmitoylation. Overactive forms of these enzymes appear to turn on oncogenes, suppress tumour-blocking genes and shift immune cells into a tumour-supporting mode. One example is the ZDHHC7 enzyme, which activates the tumour-driving protein STAT3. When STAT3 is palmitoylated, it turns on genes linked to uncontrolled cell growth. Another is ZDHHC6, which boosts levels of AEG-1, a protein that encourages cancer cells to silence protective genes. The loss of other enzymes, such as ZDHHC2, seems to remove natural checks on tumour spread. Palmitoylation also has a role in how liver cancer cells interact with their surroundings. The study shows that cancer cells use the process to reshape their membranes and even alter immune responses. CD36, a membrane protein regulated by palmitoylation, helps cancer cells absorb fats and avoid immune detection. In mouse models, altering the palmitoylation status of CD36 affects whether immune cells can recognise and attack tumours. Treatment resistance, a major obstacle in liver cancer care, is also tied to palmitoylation. The modification appears to shield certain proteins from degradation, helping cancer cells survive longer during chemotherapy. In particular, the lncRNA DUXAP8 protects cancer cells by enhancing the palmitoylation of SLC7A11, a protein that prevents cell death through ferroptosis. Targeting this pathway could open new doors for therapy. Several experimental drugs that block palmitoylation are now in preclinical or early clinical testing. These include inhibitors like tunicamycin and GNS561, which show promise in preventing tumour growth and improving the effects of standard therapies such as sorafenib. Researchers are also exploring compounds that interfere with specific targets like the TEAD family of transcription factors, which are dependent on palmitoylation for their cancer-promoting activity. As researchers continue to uncover how this fatty acid modification shapes cancer biology, palmitoylation is being repositioned from a minor curiosity to a central mechanism in liver cancer. Future therapies may aim to fine-tune this process, offering new hope to patients with a disease long known for its resistance to treatment.